Granular sustained release preparation and production thereof

ABSTRACT

There is disclosed a novel sustained release granular resin-pharmaceutical composition comprising an ion exchange resin complexed with a pharmaceutical material wherein said complex is embedded into and on the surface of a diffusion barrier material. There is also disclosed a novel process for preparing the granulated complex wherein an aqueous granulating vehicle is employed to form the complex and the granulated product, thereby avoiding the use of coatings and large amounts of organic solvents in the process.

This invention relates to granular sustained release particlescontaining pharmaceutical material.

BACKGROUND OF THE INVENTION

An early disclosure of sustained release pharmaceutical preparationsappears in U.S. Pat. No. 2,990,332 to Keating wherein a sulphonic acidcation exchange resin is employed. A pharmaceutical is ionically bondedor adsorbed onto an ion exchange resin particle. One requirement of thepharmaceutical is that it contains a basic functional group.

Thereafter, ion exchange resin drug complexes were provided with adiffusion barrier coating that provided delayed action by the gastricjuices of the person being treated with the drug. An early example ofsuch preparations is U.S. Pat. No. 4,221,778 to Raghunathan wherein theresins provided were various polymeric matrices including AMBERLITEIR120, a cationic exchange resin as well as AMBERLITE XE69, which is asmaller sized resin particle derived from AMBERLITE IR120. Other ionexchange resins mentioned were methacrylic, acrylic, phenol formaldehydeion exchange agents with cellulosic or dextran polymer matrices andinorganic ion exchange matrices. In the '778 patent, ethylcellulose wasemployed as a water-permeable, diffusion barrier coating over the ionexchange resin particle.

There followed numerous publications wherein the ion exchange resinswere treated with hydroxypropylmethyl cellulose, hydroxypropylcellulose, sorbitol, hydroxypropyl sorbitol and polyvinlylpyrrolidone.One example of this is U.S. Pat. No. 4,859,461 to Chow et al. Varyingthe thickness of the polymeric coatings provides the duration ofextended release. A variation of the organic coating of the resinparticle is disclosed in U.S. Pat. No. 4,894,239 to Nonomura et al. Inthis patent a water permeable layer is applied to the resin particle. Inone example dihydrocodeine phosphate was converted to the free base inethanol and combined with a cation exchange resin. The loaded resin wasthen separated, dried and then coated with aminoalkyl methacrylate inacetone. An eight-hour release pattern was produced by this particle.

Another approach to sustained release medication is found in U.S. Pat.No. 5,968,551 to Oshlack and Chassin, wherein a unit dose of opioid isprovided by constructing an array of different sized particles rangingin size from 0.1 mm to 3 mm. In some embodiments spherical particles areprovided but then coated with materials such as ethylcellulose orwater-soluble cellulose such as hydroxy lower alkyl cellulose. Varioussolvent coating processes are disclosed. In addition, a meltpelletization method is disclosed wherein the opioid is combined with abinder and other optional ingredients. The binder material containingthe opioid is then pelletized with a high shear mixer to obtain therequired sizes.

Another process is described in U.S. Published Application 2002/0031490.The process is based upon a resin that can be hydrated with a smallamount of water whereby the resin absorbs the active material that isrelatively insoluble in the amount of water employed. In this system theactive is at least partially dissolved in a solvent. Thus, a solventsystem is also disclosed wherein the hydrated resin is dispersed in asolvent for the active. Solvents include organic solvents such asethanol, dichloroethane and 1,1,1,2-tetrafluoroethane.

Other examples of various sustained release formulations involvingcoated resin particles include U.S. Pat. Nos. 6,001,392; 6,228,398;4,996,047; 4,959,219; 4,847,077; 4,762,709; 4,690,933 and EP 911 039.

The prior art has disclosed sustained release compositions and processesthat include a coating or coating step. It would be advantageous toprovide a sustained release pharmaceutical particle by a process thatdoes not require a polymer film coating for controlled drug deliverybecause such processes are lengthy and expensive.

SUMMARY OF THE INVENTION

In accordance with this invention, there is provided a pharmaceuticalcontaining sustained release ion exchange resin particulate materialproduced by a process that does not require a coating. The sustainedrelease particles of this invention comprise an ion exchange resincomplexed with a pharmaceutical material embedded in and on the surfaceof a granulated particulate diffusion barrier material combined by meansof a granulation process.

Rather than a continuous coating of the complex, the sustained releaseparticles of this invention comprise a diffusion barrier materialcomprising particles of granulated diffusion material having theparticles of pharmaceutical resin complex embedded into and on thesurface of the diffusion barrier material. The diffusion barriermaterial is combined with the ion exchange resin complex in agranulation process relying upon shear forces acting on the complex andparticles that form the diffusion barrier material. The granulatedparticulate sustained release material of this invention is provided bycombining a pharmaceutical material with an appropriate ion exchangeresin particle by typical means and then depositing these particles intoand on the surface of a granulated, particulate diffusion barriermaterial by means of a granulator employing a granulating vehicle. Inone embodiment of this invention, the sustained release pharmaceuticalparticles can be provided in spherical form after granulation iscompleted, without performing a further step for spheronization.Appropriate screening techniques known in the art can provide thedesired particle size.

The sustained release particles of this invention provide medication inthe body of a mammal for an extended period such as, for example, aperiod of about eight hours although other release times may beprovided. Various release times are available by the process of thisinvention by varying drug loading of the resin, and by varying the typeand amount of diffusion barrier material employed in the particle aswill be more fully disclosed below.

DETAILED DESCRIPTION OF THE INVENTION

As is known in the art, ion exchange resin particles can react withactive pharmaceutical materials to form complexes. A cation exchangeresin can form a complex with drugs containing a basic component whilean anion exchange resin can complex with drugs containing an acidiccomponent. Generally, the drug is mixed with an aqueous suspension ofthe ion exchange resin and the complex is dried. The amount ofpharmaceutical complexed to the resin may be detected by a change insolution pH, by other changes in physical properties of the complex orby a decrease in concentration of drug dissolved in the aqueous phase.

Cationic drugs are positively charged and tend to displace the cationicgroups, typically becoming complexed to the resin by ionic bonds. Sincebasic drugs are generally cationic, cationic exchange resins are oftenused to prepare drug-resin complexes with basic drugs. Typicalapproaches to forming a water insoluble drug-resin complex are to reactthe sodium salt of a cationic ion exchange resin with a cationic drug orto react the base form of the drug with the acid form of the cationicion exchange resin.

Any number of different ion exchange resins may be successfully employedin the novel practice of this invention. The ion exchange resin chosenshould not be toxic to humans and generally should not interfere withthe medicinal effect of the pharmaceutical material. Ion exchange resinsknown to be useful in the present invention are AMBERLITE IRP69 (atrademark of Rohm & Haas Chemical Co.) and the like. This resin is a geltype divinylbenzene sulfonic acid cationic exchange resin. Both cationicand anionic exchange resins may be employed in the products andprocesses of this invention. Suitable resins for the practice of theinvention include functionalized resins derived from divinylbenzenes,styrenic, methacrylic, methacrylamide, acrylic, acrylamide, carbacrylic,phenol-formaldehyde, polyhydroxy resins, polycarboxylic, carboxyvinyl,cellulosic, and dextran polymer resins. Amphoteric resins, i.e., thosederived from the above monomers but containing both anionic and cationicsites in the same polymer may also be used. Zwitterinonic resins mayalso be used in the practice of the present invention. The size range ofthe resin particles employed in this invention varies depending upon thetype of resin employed. Such resin size ranges typically from US Std.Mesh 100 to 400 (150-37 microns).

Any number of pharmaceutical active ingredients that can exist in ionicform in a semi-polar or polar solvent, such as water, are a potentialcandidate for use in the present invention. Suitable pharmaceuticalmaterials include all acidic and basic drugs. Examples include drugshaving basic groups such as amino groups, amido groups, guanidinogroups, and heterocyclic groups. Additional examples include drugs whichare carboxylic acids or amides, or which have carbonyl groups or otheracidic groups.

A large percentage of the available pharmaceutical materials are capableof forming complexes with ion exchange resins. Typical pharmaceuticalsinclude but are not limited to oxycodone hydrochloride, oxycodoneterephthalate, chlorpheniramine maleate, codeine, morphine,dextromorphan, phenylpropanolamine, pseudoephedrine, hydrocodonebitartrate, dihydrocodeine, salts and derivatives of morphine,methylephedrine, tramadol hydrochloride, ephedrine, paramino salicylicacid, phentermine, pilocarpine, metoclopramide and theophylline. Otherpossible drugs for use in the invention include all alpha-adrenergicagonists and blockers; beta-adrenergic agonists and blockers; narcoticand non-narcotic analgesics; anorexics; antiallergics; antiamebics;antianginals; antiasthmatics; antibacterials such as aminoglycosides,carbacephems, carbapenems, cephalosporins, cephamycins, penicillins,polypeptides, tetracyclines, quinolones, and sulfonamides;anticholinergics; antidepressants; antifungals; nonsteroidalanti-inflammatories; antispasmodics; antiulceratives; antivirals;anxiolytics; calcium channel blockers; dopamine receptor agonists andantagonists; narcotic antagonists; protease inhibitors; respiratorystimulants; retroviral protease inhibitors; reverse transcriptaseinhibitors; sedatives such as benzodiazepine derivatives; and cerebral,coronary, and peripheral vasodilators. Of course, depending on the pKaof the pharmaceutical, either an anionic or cationic exchange resin willbe selected. In some cases, an amphoteric resin may be used depending onthe physicochemical properties of the pharmaceutical, i.e., pKa as wellas binding constants.

Many other pharmaceutical materials may be employed in the sustainedrelease particles and process of this invention. Numerous such examplesare known in the art and particularly in the aforementioned U.S. Pat.No. 2,990,332 to Keating that is incorporated herein by reference.

The sustained release particles of this invention typically contain fromabout 5% to about 80% by weight of a pharmaceutical material. A morepreferred amount of pharmaceutical content of the particles of thisinvention is from about 10% to about 60% by weight and a more preferredrange of pharmaceutical content of the particles of this invention isfrom about 10% to about 50% by weight.

In the process of this invention, a suspension of the ion exchange resinis formed and the pharmaceutical material is applied to the resinparticle suspension. Alternatively, the ion exchange resin may be addedto a suspension or solution of the pharmaceutical material. Ionic forcesprovide complexation of the pharmaceutical material with the resin.

The prepared resin-pharmaceutical complex is then ready to be introducedto a diffusion barrier material in a low or high shear granulationprocess employing a granulation vehicle. The granulation vehicleincludes water and mixtures of water and alcohol. The release profile ofthe sustained release particles of the invention may be modified byvarying the amount of alcohol in the mixture. In one embodiment, thediffusion barrier material is introduced into the granulation apparatusfirst with an aqueous granulation vehicle wherein some hydration of thediffusion barrier material takes place.

After the diffusion barrier material has been added to the granulationdevice, the above noted resin-pharmaceutical complex is combined withthe diffusion barrier material. While not bound by any theory, it isbelieved that shear forces allow binding of the resin-pharmaceuticalcomplex into and on the surface of the particulate diffusion barriermaterial. The diffusion barrier material is not required to completelycover particles of the resin-pharmaceutical complex.

Preferably, a high shear granulation process is employed. Typical highshear granulators useful in the process of this invention are Model VG-5granulator or Model VG-25; both manufactured by Powrex Corp.

Any number of diffusion barrier layer materials can be employed in thesustained release particles of this invention. Such materials of coursemust be inert to the pharmaceutical material and non-toxic. Typicaldiffusion barrier materials include but are not limited toethylcellulose and microcrystalline cellulose or mixtures thereof,polymethacrylates and polyacrylates and copolymers thereof, chitosan,starch and lactose or combinations of starch or lactose withmicrocrystalline cellulose. Examples of polymethacrylates are materialsold under the trade name Eudragit® by Rohm Pharma GmbH. In oneembodiment, the diffusion barrier material is a combination ofethylcellulose and microcrystalline cellulose. Typically, the nominalmean particle size of the diffusion barrier material is in the range offrom about 20 to about 180 microns although other size ranges may beemployed.

After granulation, the product is dried and sized by typical means. Anysuitable drying means such as a fluid-bed dryer may be employed. Furthertreatment of the product may occur if desired. The granulation processmay provide particles of irregular shape. In some instances, a sphericalshape is desired. To make the product into spheres, the product from thegranulation process may be extruded into small thin rods. The rods aretypically produced by forcing the material through a die containingholes in the range of from about 0.5 mm to about 5 mm and made intospheres by typical means. One such means to provide spherical shapedparticles is to introduce the rods into a spheronizer. The spheres arethen sieved to a desired size range. In another embodiment, thesustained release pharmaceutical particles can be provided in sphericalform after granulation is completed, without performing a further stepfor spheronization. For example, in granulating with a high sheargranulator, a controlled granule growth is accompanied by furtherdensification of the granules and embedding of the resin-pharmaceuticalcomplex within the diffusion barrier material. Following the drying ofthe granules, no further treatment is necessary to provide an extendedrelease of the pharmaceutical material.

The sustained release particles of this invention may be included in avariety of dosage forms such as powders, capsules, liquid suspensions orother conventional dosage forms. Of particular utility is the hard orsoft gelatin capsule combining a combination of sustained releaseparticles carrying differing pharmaceutical materials.

The following examples are intended to illustrate the present inventionand are not to limit the claims in any manner. All of the percentagesare by weight unless otherwise indicated.

EXAMPLE 1

One thousand grams of ion-exchange resin AMBERLITE IRP69, marketed byRohm and Haas Chemical Co., having a US Std. Mesh size in the range of100 to 400 were suspended in 2 liters of deionized water. Hydrocodonebitartrate, 600 g, was dissolved in 6 liters of deionized water andadded to the aqueous resin suspension with stirring. The mixture wasstirred for 2 hours at room temperature. The suspension was thenfiltered through a Buchner funnel and washed three times with 1 liter ofdeionized water each. The washed filter cake was dried in a fluid-beddrier to a final moisture content of about 10%. The dry powder(hydrocodone-resin complex; HC-resinate) was analyzed by HPLC anddetermined to have a hydrocodone content equivalent to 45% by weight ofhydrocodone bitartrate.

A high shear granulator was fitted with a 5-liter bowl and charged with100 g of HC-resinate from above. Deionized water (100 g) was sprayedonto the complex and mixed for about 5 minutes. One hundred grams ofethylcellulose powder was added to the granulating bowl and mixed for 5minutes followed by the addition of 200 g of microcrystalline cellulosesold under the trade name Avicel PH-101 (product of FMC Corp.) andblended for an additional 6 minutes. The wet mixture was granulated with339.9 g of deionized water. The wet granules were divided into twoportions A and B).

Portion A was sieved through a US Std. Mesh #6 screen and fluid-beddried. The dry granules were sieved through US Std. Mesh #16 and #20screens and marked as Sample A. HPLC analysis of the fraction showedthat the hydrocodone content was equivalent to 8.9% by weight ofhydrocodone bitartrate. A dissolution test was performed in 0.1N HCl(Paddles; 100 rpm; 500 ml; N=3) and the data reported in Table 1 below.

The unsieved Portion B was extruded into thin rods using an LCILaboratory Dome Granulator (model DG-L1) employing a 0.8 mm die. Thethin rods were made into spheres using a Marumerizer (manufactured byFuji Paukal Co., Ltd). The spheres were dried by means of a fluid-beddryer. The spherical particles thus produced were sieved and the US Std.Mesh −16+20 fraction was analyzed by HPLC showing the granules contained8.9% by weight hydrocodone bitrate. Portion B was marked as Sample B. Adissolution test was performed by the procedure indicated above for thisportion and the data obtained are presented in Table 1 below.

TABLE 1 SAMPLE NO. A B Manufacturing Process GranulationExtrusion/Marumerization Dissolution Data Cumulative % DissolvedCumulative % Dissolved Time (minutes) Mean SD Mean SD 15 14.0 1.9 12.30.9 30 22.9 1.8 20.6 0.5 60 34.6 1.0 31.0 0.6 120 48.0 0.3 43.8 0.9 18058.3 0.3 53.3 0.8

Sustained release ion-exchange resin complexes can be achieved by agranulation process alone or by extrusion-marumerization process asshown by the data in Table 1 above. Such processes are achieved withoutuse of a coating process or organic solvent in any step.

EXAMPLE 2

A batch of hydrocodone-resin complex was prepared as in Example 1 withthe exception that the wet cake was not dried but was in the wet statewhen introduced into the granulation process. The wet hydrocodone-resincomplex, 183.3 g, moisture content of 45.43%, was granulated with 200 gof ethylcellulose (Ethocel Standard 10FP Premium marketed by DowChemical Co.), 100 g microcrystalline cellulose (Avicel PH-101) and228.42 g deionized water. The wet granules were sieved through a US Std.Mesh # 10 screen and dried in a fluid-bed drier to a final moisturecontent of 4.2% and marked Sample C. The dry granules were then sievedthrough US Std. Mesh #16 and #20 screens. The −16+20 fractions wereanalyzed by HPLC and by dissolution test as in Example 1. The data arereported in Table 2 below.

EXAMPLE 3

The procedure of Example 2 was repeated except that the granulationmatrix was only 300 g of Avicel PH-101 together with 181.8 g of wethydrocodone-resin complex. The final product was marked Sample D. The−16+20 fractions were analyzed by HPLC and by dissolution test as inExample 1. The data are reported in Table 2 below.

EXAMPLE 4

The procedure of Example 2 was repeated with the exception that thegranulation matrix was 200 g of Avicel PH-101, 200 g of ethylcelluloseand 181.8 g of the wet hydrocodone-resin complex. The final product wasmarked Sample E. The dry granules were sieved as in Example 2 and the−16+20 fractions were analyzed by HPLC and by the dissolution test asdescribed in Example 1. The data are presented in Table 2 below.

TABLE 2 Lot No Sample C Sample D Sample E Hydrocodone Content 9.7% 8.4%8.7% Dissolution Data-Cumulative % Released Time (minutes) Mean SD MeanSD Mean SD 15 13.2 1.4 20.4 2.8 17.9 0.7 30 22.3 1.6 29.8 4.0 28.0 1.060 35.6 3.3 40.4 3.7 40.4 1.6 120 49.8 3.1 53.7 4.0 55.3 2.0 180 58.12.9 62.1 3.1 63.7 0.9

Varying the matrix suitably may modify release profile.

EXAMPLE 5

Particles of ion exchange resin AMBERLITE IRP69, 1.5 kg having a sizerange of US Std. Mesh #100-#400 were suspended in 6 kg of USP water.Hydrocodone bitartrate, 900 g was added in one step to the resinsuspension with stirring. The mixture was stirred for 1 hour at roomtemperature, filtered through a sintered glass funnel, and washed threetimes with 1.5 kg of USP water each.

To a 25-liter bowl of a Powrex Hi-Shear granulator were charged 2.55 kgof microcrystalline cellulose, Avicel PH-101. The Avicel was wetted with0.96 kg of USP water. Granulation parameters were set as follows: Mainblade: 200 rpm, Cross-screw: 400 rpm, Water addition rate: 97 g/minute.After all the water had been added, 0.806 kg of the wet HC-resinate cakefrom above was added and mixed for 6 minutes. The mixture was granulatedwith 1.316 kg of USP water. Granulation parameters were: Main Blade: 60rpm; Cross-screw: 600 rpm; Water addition rate: 133 g/minute. After allthe water had been added, the mixture was blended for an additional 6minutes. The resulting wet granules were sieved through a US Std. Mesh#4 screen and dried in a fluid-bed drier to a final moisture content of4.70%. The dry granules were first sieved through a US Std. Mesh #16screen and then with a #40 screen. The yield of the −16+40 fractions was2.081 kg and the combined fractions were analyzed by HPLC forhydrocodone content. The product was marked Sample F. The data for sixreplicate tests of the dissolution test as described in Example 1 abovewas performed and the data for this product are presented in Table 3below.

EXAMPLE 6

Particles of ion-exchange resin AMBERLITE IRP69 (1.5 kg; US Std. Mesh#100-#400) were suspended in 6 kg of USP water. Hydrocodone bitartrate,900 g was added all at once to the resin suspension with stirring. Themixture was stirred for 1 hour at room temperature, filtered through asintered glass funnel, washed three times with 1.5 kg of USP water each.

To a 25-liter bowl of a Powrex Hi-Shear granulator were charged 2.250 kgof microcrystalline cellulose (Avicel PH-101). The Avicel was wettedwith 0.850 kg of USP water and granulated. Granulation parameters were:Main blade: 200 rpm; Cross-screw: 400 rpm; Water addition rate: 87g/minute. After all the water had been added, 1.391 kg of the wet cakefrom above was added and the mixture was blended for an additional 6minutes. The mixture was granulated with 1.491 kg of USP water. Thegranulation parameters were: Main blade: 60 rpm; Cross-screw: 600 rpm;Water addition rate: 122 g/minute. After all the water had been added,the mixture was blended for an additional 6 minutes. The resulting wetgranules were sieved through a US Std. Mesh #4 screen and dried in afluid-bed drier to a final moisture content of 3.90%. The dry granuleswere first sieved through a US Std. Mesh #16 screen and then with a #40screen. The yield of the −16+40 fraction was 1.957 kg. The product wasmarked Sample G and analyzed by HPLC to determine the hydrocodonecontent. The data for six replicate tests of dissolution rate for thisproduct are shown in Table 3 below. The tests were conducted as notedabove in Example 1.

EXAMPLE 7

Particles of ion-exchange resin AMBERLITE IRP69, 1.5 kg, US Std. Mesh#100-#400, were suspended in 4 kg of USP water. The suspension waswarmed to 30°-35° C. Chlorpheniramine maleate, 300 g, was added all atonce to the resin suspension with stirring. The mixture was stirred for1 hr. at 30°-35° C., filtered through a sintered glass funnel and washedthree times with 1.5 kg of USP water each time to provide a wet cake(CP-resinate).

The 25-liter bowl of a Powrex Hi-Shear granulator was charged with 1.5kg of microcrystalline cellulose, Avicel PH-101. The Avicel was wettedwith 0.570 kg of USP water. Granulation parameters were: Main blade: 80rpm; Cross-screw: 400 rpm; Water addition rate: 58 g/minute. After allthe water had been added, 3.151 kg of the wet cake, CP-resinate, fromthe above were added and mixed for 6 minutes. The mixture was granulatedwith 1.651 kg of USP water. Granulation parameters were: Main blade: 60rpm; Cross-screw: 600 rpm; Water addition rate: 102 g/minute. After allthe water had been added, the mixture was blended for an additional 6minutes. The resulting wet granules were sieved through a US Std. Mesh#4 screen and dried in a fluid-bed drier to a final moisture content of5.31%. The dry granules were first sieved through a US Std. Mesh #16screen and then with a #40 screen. The yield of the −16+40 fraction was1.450 kg with a moisture content of 5.31%. The product was marked SampleH and the −16+40 fraction was analyzed by HPLC for chlorpheniraminecontent. The data for six replicate tests of dissolution rate for thisproduct are shown in Table 3 below. The tests were conducted as notedabove in Example 1.

EXAMPLE 8

Particles of ion-exchange resin AMBERLITE IRP69 (1.5 kg; US Std. Mesh#100-#400) were suspended in 4 kg of USP water. The suspension waswarmed to 30°-35° C. Chlorpheniramine maleate (300 g) was added all atonce to the resin suspension with stirring. The mixture was stirred for1 hour at 30°-35° C., filtered through a sintered glass funnel, washedthree times with 1.5 kg of USP water each.

The 25-liter bowl of a Powrex Hi-Shear granulator was charged with 2.250kg of microcrystalline cellulose, Avicel PH-101. The Avicel was wettedwith 0.850 kg of USP water. Granulation parameters were: Main blade: 200rpm; Cross-screw: 400 rpm; Water addition rate: 86 g/minute. After allthe water had been added, 1.522 kg of the wet cake from the above wasadded and mixed for 6 minutes. The mixture was granulated with 1.622 kgof USP water. Granulation parameters were: Main blade: 60 rpm;Cross-screw: 600 rpm; Water addition rate: 122 g/minute. After all thewater had been added, the mixture was blended for an additional 6minutes. The resulting wet granules were sieved through a US Std. Mesh#4 screen and dried in a fluid-bed drier to a final moisture content of4.40%. The dry granules were first sieved through a US Std. Mesh #16screen and then with a #40 screen. The yield of the −16+40 fraction was2.105 kg. The product was marked as Sample I and subjected to HPLCanalysis for chlorpheniramine content. The data for six replicate testsof dissolution rate for this product are shown in Table 3 below. Thetests were conducted as noted above in Example 1.

TABLE 3 Product SAMPLE SAMPLE SAMPLE SAMPLE F G H I Active Drug ContentHydrocodone Chlorpheniramine 10% 6.3% 8.4% 4.3% DissolutionData-Cumulative % Released Time (hrs.) Mean SD Mean SD Mean SD Mean SD0.25 32.8 2.7 21.5 1.3 40.7 7.1 21.6 1.5 0.5 45.4 4.0 32.3 1.6 51.4 5.330.9 1.5 1 58.3 4.6 44.4 2.0 61.0 5.8 40.5 2.6 2 70.5 4.8 57.4 2.4 68.34.7 50.8 2.8 3 76.9 4.1 64.8 2.3 71.6 3.8 56.7 2.9 6 84.4 3.4 76.2 1.974.7 3.1 66.1 2.6 8 86.7 2.7 80.4 1.9 75.6 2.6 69.6 2.4

EXAMPLE 9

Hydrocodone polistirex was prepared by mixing 4.00 kg of hydrocodonebitartrate with 4.76 kg of ion-exchange resin particles (ABMERLITEIRP69; US Std. Mesh #100-#400) suspended in USP water at about 70° C.The resulting suspension was centrifuged and the product washed with USPwater. The wet cake was dried and sieved through a US Std #30 meshscreen. The hydrocodone content of the dried product was equivalent toapproximately 56% by weight of hydrocodone bitartrate.

A Powrex Hi-Shear granulator fitted with a 50-liter bowl was chargedwith 6.480 kg of microcrystalline cellulose (Avicel PH-101). USP water(2.398 kg) was added to the Avicel, with the main blade of thegranulator at 200 rpm and the cross-screw at 400 rpm. The water additionrate was 0.2 kg/minute. Hydrocodone polistirex (0.720 kg) prepared asabove was then added to the granulator and mixed with the Avicel for 6minutes. The granulator parameters were: Main blade: 200 rpm;Cross-screw: 400 rpm. USP water (3.942 kg) was added to the mixture inthe granulator at a rate of 0.2 kg/minute. The granulator parameterswere: Main blade: 60 rpm; Cross-screw: 600 rpm. After all the water hadbeen added, the wet mass was blended for an additional 6 minutes. Thegranulator parameters were: Main blade: 60 rpm; Cross-screw: 600 rpmduring the additional 6 minutes. The product was discharged from thegranulator and sieved through a US Std. Mesh #4 screen to yield 13.31 kgof wet granules. Approximately 3.3 kg of the sieved wet granules werespheronized using a Marumerizer fitted with a 4-liter bowl and afriction plate with 2-mm grooves. The plate speed and marumerizationtimes were about 400 rpm and 4 minutes respectively. The wet sphericalgranules were then dried in a fluid-bed processor and the final moisturecontent was found to be 2.0%. The marumerization step was repeated untilall the wet granules had been spheronized. The granulation step wasrepeated several times to make several kg of the dry HP granules. Allthe dry HP granules were combined and sieved through a US Std. Mesh #18screen. A representative sample of the final product was analyzed byHPLC for hydrocodone content. The hydrocodone content was determined tobe equivalent to 5.5% by weight. The data for six replicate tests ofdissolution rate for this product are shown in Table 4 below. The testswere conducted as noted in Example 1.

EXAMPLE 10

Chlorpheniramine polistirex was prepared by mixing 3.12 kg ofchlorpheniramine maleate with 26.00 kg of ion-exchange resin particles(AMBERLITE IRP69; US Std. Mesh #100-#400) suspended in USP water atabout 30° C. The resulting suspension was centrifuged and the productwashed with USP water. The wet cake was dried and sieved through a USStd #30 mesh screen. The chlorpheniramine content of the dried productwas equivalent to approximately 11% by weight.

A Powrex Hi-Shear granulator was fitted with a 50-liter bowl and chargedwith 3.960 kg of microcrystalline cellulose (Avicel PH-101). USP water(1.465 kg) was added to the Avicel, with the main blade of thegranulator at 200 rpm and the cross-screw at 400 rpm. The water additionrate was 0.2 kg/minute. Chlorpheniramine polistirex (3.240 kg) preparedas above was then added to the granulator and mixed for 6 minutes. Thegranulator parameters were: Main blade: 200 rpm; Cross-screw: 400 rpm.USP water (4.996 kg) was added at a rate of 0.2 kg/minute. Thegranulator parameters were: Main blade: 60 rpm; Cross-screw: 600 rpm.After all the water had been added, the wet mass was blended for anadditional 6 minutes. The granulator parameters were: Main blade: 60rpm; Cross-screw: 600 rpm. The product was discharged from thegranulator and sieved through a US Std. Mesh #4 screen to yield 13.55 kgof wet granules. Approximately 3.3 kg of the sieved wet granules werespheronized using a Marumerizer fitted with a 4-liter bowl and afriction plate with 2-mm grooves. The plate speed and the marumerizationtime were about 1000 rpm and 5 minutes respectively. The wet sphericalgranules were then dried in a fluid-bed processor and the final moisturecontent was found to be 4.3%. The marumerization step was repeated untilall the wet granules had been spheronized. The granulation step wasrepeated several times to make several kg of the dry CP granules. Allthe CP granules were combined and sieved through a US Std. Mesh #18screen. A representative sample of the final product was analyzed byHPLC for chlorpheniramine content. The chlorpheniramine content wasdetermined to be equivalent to 5.2% by weight. The data for sixreplicate tests of dissolution rate for this product are shown in Table4 below. The tests were conducted as noted in Example 1.

TABLE 4 Example 9 Example 10 Active Drug Hydrocodone ChlorpheniramineContent 5.5% 5.2% Dissolution Data-Cumulative % Released Time (hrs.)Mean SD Mean SD 0.25 14.4 2.8 29.3 2.6 0.5 25.6 3.6 39.9 2.6 1 39.0 4.049.6 3.3 2 54.4 3.9 59.8 4.0 3 64.2 3.6 63.4 3.5 6 78.7 2.1 68.7 3.0 885.0 1.6 70.5 2.7

Oral dosage forms were prepared by filling gelatin capsules with the HPand CP granules made as above.

Decreasing the level of resin-drug complex in the granulation matrix mayslow release of the pharmaceutical. Different pharmaceutical agents mayhave different release rates due to the strength of thepharmaceutical-resin complex.

Although the invention has been described in terms of specificembodiments which are set forth in considerable detail, it should beunderstood that this description is by way of illustration only and thatthe invention is not necessarily limited thereto since alternativeembodiments and operating techniques will become apparent to thoseskilled in the art in view of the disclosure. Accordingly, modificationsare contemplated which can be made without departing from the spirit ofthe described invention.

1. A non-coated, sustained release pharmaceutical composition consistingof a plurality of granules, the granules consisting of: (i) about 10% toabout 60% by weight of a non-coated complex particulate comprising anion consisting of a styrene-divinylbenzene sulfonic acid cationicexchange resin and a pharmaceutically active material complexed with theion exchange resin, the pharmaceutically active material being selectedfrom the group consisting of oxycodone hydrochloride, tramadolhydrochloride, dextromethorphan, hydrocodone bitartrate,chlorpheniramine maleate, codeine, morphine or morphine salt,hydrocodone, phenylpropanolamine, pseudoephedrine, dihydrocodeine,methylephedrine, ephedrin, paraamino salicylic acid, phentermine,pilocarpine, metoclopramide and theophylline; and, (ii) a non-coated,granulated water-insoluble matrix consisting of microcrystallinecellulose, wherein the non-coated, complex particulate is embedded intothe non-coated, granulated water-insoluble matrix of microcrystallinecellulose, and further wherein the non-coated, granulatedwater-insoluble matrix of microcrystalline cellulose sustains release ofthe pharmaceutically active material from the non-coated, complexparticulate.
 2. The non-coated composition of claim 1 wherein theinitial resin particle size is in the range of US Std. Mesh sizes fromabout #10 to about #400.
 3. The non-coated composition of claim 1wherein the pharmaceutically active material is hydrocodone bitartrate.4. The non-coated composition of claim 1 wherein the pharmaceuticallyactive material is chlorpheniramine maleate.
 5. The non-coatedcomposition of claim 1 wherein the non-coated, granulatedwater-insoluble matrix of microcrystalline cellulose sustains release ofthe pharmaceutically active material from the complex particulate forabout 8 hours.
 6. The non-coated composition of claim 5 wherein thenon-coated, granulated water-insoluble matrix of microcrystallinecellulose sustains release of the pharmaceutically active material fromthe complex particulate for about 8 hours when granules of thenon-coated composition are placed in a 0.1 N HCl solution and agitatedat 100 rpm.
 7. The non-coated composition of claim 1 wherein thegranules consist of about 10% to about 50% by weight of the non-coatedcomplex particulate.
 8. The non-coated composition of claim 1 whereinthe microcrystalline cellulose has a nominal mean particle size of fromabout 20 to about 180 microns.